The Fragile X Mental Retardation 1 (FMR1) gene is located on the X chromosome and encodes the polysome-associated RNA-binding protein FMRP, which plays key roles in neuronal development and synaptic plasticity through the regulation of mRNAs at the level of traffic, stability, splicing and both somatic and presynaptic translation [1]. The 5′-UTR of the FMR1 gene contains a stretch of CGG repeats that causes a series of pathological conditions when exceeding 54 repeats, although there is increasing evidence of an association between the “gray zone”, ranging from 45 up to 54 triplet copies (which forms an unstable FMR1 allele that can be expanded in successive generations [2]) with atypical parkinsonism [3]. The silencing of the FMR1 gene occurs over 200 CGG repeats (the so-called full mutation, FM), resulting in severe diminished FMRP expression during development and in consequence the onset of the Fragile X syndrome (FXS, OMIM #300624). FXS is the most common cause of monogenic intellectual disability, with a high incidence of autistic features, hyperactivity behaviour and seizures, and usually accompanied by macroorchidism and distinct facial features [4].

The so-called premutation (PM), whose carriers can exhibit diverse symptomatology comprising both neural and non-neural pathological traits with different degrees of severity and compromised well-being, is defined in the range of 55 and 200 repeats. The worldwide prevalence of the PM is approximately 1:300 in females and 1:850 in males [5]. The risk to develop FXTAS (OMIM #300623) is higher in men than in women: from 17% to 75% of the PM male carriers as age increases, and only from 8 to 16% in PM carrier women [6,7] who exhibit a diverse phenotype much milder than those observed in men, possibly due to the female inactivation of chromosome X [8]. FXTAS is a late onset neurodegenerative disorder characterized by intention tremor usually accompanied by slow movement and parkinsonism, which develop into cerebellar gait ataxia and dystonia as the disease progresses, and by cognitive deficits (e.g., short-term memory loss, executive functions impairment, language capacity affectation), mood disorders and neuropsychiatric alterations, peripheral neuropathy, sleep disturbance and other signs [6,9,10]. The main radiological signs consist of an increased signal in brain white matter, especially in the middle cerebellar peduncles (MCP) in men [11]. MCP are the main afferent pathway to the cerebellum and are primarily composed by white fibers projected from the contralateral pontine nuclei as part of the cortico-ponto-cerebellar pathway that control motor tasks, planning and initiation of movements [12]. In addition, FXTAS patients show smaller volume in overall brain and particularly cerebellum related to PM carriers without diagnosis [13]. The presence of eosinophilic intranuclear ubiquitin-positive inclusions in brain, spinal cord and peripheral tissues is a hallmark of this disorder [14,15,16].

More prevalent in women is the development of the Fragile X-associated primary ovarian insufficiency (FXPOI, OMIM #311360): 24% of the PM women whereas the prevalence of POI in the general population is 1% [17]. This form is the most common inheritable ovarian dysfunction, which symptoms include irregular menstruation cycles, reduced fertility and early menopause onset [18]. More precisely, FXPOI involves ovarian hormonal dysfunction alongside with follicle depletion before the age of 40 years, having a direct impact on menstrual cycle regularity (that can lead to amenorrhea) and the ability to conceive, together with a variety of indirect consequences derived from chronic hypoestrogenism, such as early onset of osteoporosis and bone fracture, impaired vascular endothelial function, earlier onset of coronary heart disease and increased cardiovascular mortality, and higher risk of psychiatric symptomatology (e.g., anxiety, depression, etc.) than women with normal ovarian functionality [19,20,21,22,23,24].

2. Is There a Fragile X Spectrum Disorder?